Objective: This study aimed to evaluate the resistance of Helicobacter pylori (H. pylori) to common antibiotics in Shanghai. Methods: A total of 1171 eligible subjects participated in the study. Antibiotic susceptibility to six common antibiotics was examined with the disk diffusion method. Mutations in resistant-related genes were identified via Sanger sequencing analysis. Results: Overall, the resistance rates of strains to amoxicillin, clarithromycin, levofloxacin, metronidazole, tetracycline, and furazolidone were 0.1%, 27.8%, 31.1%, 79.9%, 0.1%, and 0.5%, respectively. Compared with untreated patients, resistance rates of clarithromycin (P < 0.01), levofloxacin (P < 0.01), and metronidazole were signifi cantly higher in re-treated patients (P < 0.05). The total multiple resistance rate was 40.5%. Age (levofloxacin), gender (clarithromycin, levofloxacin, and metronidazole) and endoscopic fi ndings (clarithromycin and levofloxacin) were independent factors influencing antibiotic resistance. High correlation was observed between the drug susceptibility test and molecular test for the resistance to clarithromycin and levofloxacin. Conclusions: The resistance rates of H. pylori to amoxicillin, tetracycline, and furazolidone were low, whereas the resistance rates of H. pylori to clarithromycin, levofloxacin, and metronidazole were high, especially in re-treated patients. Our results indicate that the clinical resistance patterns of clarithromycin and levofloxacin could be guided by relevant gene mutations.